WO2012140365A1 - Use of calixarenes associated with an antibiotic in the treatment of bacterial infections - Google Patents

Abstract

The invention relates to a product comprising at least one given antibiotic and a calixarene for use as a drug.

Description

 USE OF CALIXARENES ASSOCIATED WITH ANTIBIOTICS IN THE TREATMENT OF BACTERIAL INFECTIONS

The present invention relates to the use of calixarenes with an antibiotic in the treatment of bacterial infections.

 In the field of public health, the fight against community or nosocomial bacterial infections is still a subject of topicality and concern. Indeed, bacteria are the microorganisms most often responsible for nosocomial infections (IN), with, in order of frequency: Escherichia coli (24.7%), Staphylococcus aureus (18.9%), Pseudomonas aeruginosa (10% ) and Enterococcus spp. (6%) (RAISIN Survey 2006).

 Some clinically involved bacteria have resistance or even resistance to antibiotics and / or antiseptics used routinely. We talk about BMR for Multi-Resistant Bacteria and BTR for Toto-Resistant Bacteria. There may be mentioned, for example, S ARMs (Staphylococcus aureus resistant to Meticillin, with resistance to all β-Lactamines), Enterobacteria carrying ESBL (Extended Spectrum Beta-Lactamase) or ERG (Enterococcus spp. Resistant to Glycopeptides). At present, 64%> of Staphylococcus aureus isolated during IN are meticillin-resistant (Survey RAISIN 2006). The problem is that bacteria often carry several resistance mechanisms, inducing resistance to many families of antibiotics: β-lactams, aminoglycosides, fluoroquinolones or macrolides ... Moreover, this resistance to antibiotics, is often associated with a resistance to antiseptics, used in hospital, to fight against the spread of nosocomial infections.

 The resistance of a bacterial strain to an antibiotic may be a natural resistance (characteristic of all strains of the same species). It can also be acquired (characteristic of certain strains within a species); it then results from a modification of the genetic capital of these bacteria. This kind of genetic modification can confer on a particular bacterial strain a mechanism of resistance to an antibiotic, a family of antibiotics or several families of antibiotics.

Basic research on the mechanisms involved in bacteria and epidemiological information currently raises doubts about the possibility of eradicating BMRs in the future. Therefore, it is no longer certain that currently available antibiotics can sustainably control the problem. If the availability of new antibiotics has allowed until today to respond to each form of bacterial resistance, this approach now faces many limitations, since no new class of antibiotics has been developed in twenty-five years (Boucher et al., CID, 2009). Few new antibiotics have been marketed since the early 1990s. Among these new antibiotics, only linezolid and daptomycin, have an innovative mechanism of action, but are reserved for specific applications and are active only on bacteria. Gram positive. In addition, they exhibit significant toxicity (hematologic and medullary toxicity for linezolid, eosinophilic pneumopathies for daptomycin), which has limited their use.

 However, soon after their commercialization, resistance appeared. Thus, by way of example, mention may be made of the cases of linezolid, daptomycin, quinupristin-dalfopristin, or tigecycline, including in bacteria initially BMR.

 By bringing into play an innovative concept linking supramolecular chemistry with targeting and disruption of the bacterial envelope, a new family of antibacterial compounds, in particular para-guanidinoethylcalix [4] arene, hereinafter referred to as Cxi, has recently been developed. This family of compounds has antibacterial properties vis-à-vis various bacteria involved in nosocomial and / or community infections.

 The publication of Grare et al. (J. Antimicrob Chemother, 60 (2007), 575-581) discloses that Cxi has antibacterial activity on antibiotic-resistant and non-antibiotic-resistant bacteria.

 In the publication of Grare et al. (Clin Microbiol, Infect 16 (2010), 432-438), the antibacterial activity of Cxi is compared with that of hexamidine and chlorhexidine, two antiseptics, widely used in human therapy, on a series of clinical isolates: MDR ("multidrug resistant"), XDR ("extended drug resistant") or PDR ("pan-drug resistant").

 The article by Grare et al. (Pathology Biology 58 (2010), 46-51) describes that Cxi, as a cationic antibacterial, interacts with the bacterial wall, ultimately resulting in a loss of membrane integrity.

Nevertheless, faced with the threat of the appearance of PDR bacteria, the absolute urgency remains to have available new antibacterial compounds with innovative mechanisms of action to treat patients infected with this type of bacteria; and / or new means for rendering the treatment with antibiotics normally used in anti-infectious therapy, again accessible to these patients. One aspect of the present invention is to provide novel antibacterial products.

Another aspect of the invention is to provide novel antibacterial compositions associating calixarenes and antibiotics.

 The present invention is based on an unexpected finding by the inventors, when evaluating the antibacterial activity of para-guanidinoethylcalix [4] arene, hereinafter referred to as Cx1. This molecule makes it possible to reduce the MIC (Minimal Inhibitory Concentration) of an antibiotic against which a bacterial strain has a resistance.

 In other words, on the one hand, Cx1 makes it possible to confer de novo a certain level of sensitivity with respect to (an) antibiotic (s) in a bacterial strain having acquired resistance to said antibiotic (s). (s), and on the other hand, Cx1 is also capable of conferring susceptibility to (a) antibiotic (s) in a bacterial strain having a natural resistance to said antibiotic (s) .

 Specifically, in the clinical setting, the treatment of Cxl in combination with the treatment of at least one antibiotic can reduce the dose of the latter in the context of the treatment of an infection with a bacterium resistant to said antibiotic, and / or render the treatment with said antibiotic effective for patients having an infection with at least one bacterial strain resistant to said antibiotic.

The present invention provides a product comprising at least one given antibiotic, and a calixarene represented by the following formula I:

Formula I

dans laquelle :

in which :

 (i) n = an integer of 4 to 16,

 (ii) m = an integer of 1 to 10,

 (iii) X is selected from:

 a hydrogen,

an alkyl group, the number of carbons being from 1 to 20, in particular from 1 to 10, a halogen chosen from Cl, Br, I, or

an amphiphilic group chosen from an anionic group, such as the carboxylates -RC0 ₂ ^~ , the sulphates -RSO ₄ ^" , the sulphonates -RSO ₃ ^" , a cationic group, such as RNH ₃ ⁺ , in which R is an alkyl group the number of carbons being from 1 to 20, in particular from 1 to 10,

for its use as a medicine.

In a particular embodiment, the product according to the invention comprises a given antibiotic and a calixarene represented by the formula I, wherein n = 4, said calixarene represented by the following formula 1 (1):

Formula 1 (1)

m and X having the meanings indicated above.

 In another particular embodiment, the product according to the invention comprises a given antibiotic and a calixarene represented by the formula I, wherein m = 1, said calixarene represented by the following formula 1 (2):

Formula 1 (2)

n and X having the meanings indicated above. According to another particular embodiment, the product according to the invention comprises a given antibiotic and a calixarene represented by the formula I, in which X is a hydrogen, said calixarene represented by the following formula 1 (3):

Formula 1 (3)

m and n having the meanings indicated above.

In an advantageous embodiment, the present invention relates to a product for use as a medicament, said product comprising a given antibiotic and a calixarene represented by formula I, wherein n = 4, m = 1 and X is hydrogen, said calixarene represented by the following formula II:

Formula II

The molecule represented by formula II is para-guanidinoethylcalix [4] arene, designated Cxi in the present invention.

The three-dimensional structure of the above-mentioned molecule is illustrated below.

Cx1 can be synthesized according to the method described in Mourer et al. (Bioorganic & Medicinal Chemistry Letter 16 (2006) 2960-2963).

 The calixarene according to the invention may be as described above, or a physiologically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH ).

 The term "physiologically acceptable acid salt" means a derivative of a compound of formula I, obtained by reacting an inorganic acid or an organic acid, with a compound of formula I.

 Examples of inorganic acids for obtaining physiologically acceptable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, formic acid monohydrogenocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid, hydroiodic acid.

 Examples of organic acids for obtaining physiologically acceptable salts include, but are not limited to, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, lactic acid, palmic acid, maleic acid, glutamic acid, hydroxymaleic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid.

Amino acid salts, such as arginates and their equivalents are also included as well as salts of organic acids such as glucuronic acid or galacturonic acid and their equivalents (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). The given antibiotic used in the aforementioned product for its use as a medicament according to the invention may be chosen from β-lactams, aminoglycosides, fluoroquinolones, fosfomycin, colimycin, rifampicin, tigecycline, or fusidic acid, and more particularly in the group comprising imipenem, piperacillin-tazobactam, penicillin G, cefotaxime, ceftazidime, tobramycin, gentamicin, ciprofloxacin, rifampicin, fosfomycin, colimycin, streptomycin, ticarcillin-clavulanic acid, tigecycline or fusidic acid. In a particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and tigecycline.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and fusidic acid.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and fosfomycin.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and penicillin.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by the formula II (Cx1) and imipenem.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and gentamicin.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and cefotaxime.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and rifampicin.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and piperacillin-tazobactam.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and ciprofloxacin.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and ceftazidime.

In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and colimycin. In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and ticarcillin-clavulanic acid.

 In another particularly advantageous embodiment, the product according to the invention comprises a calixarene represented by formula II (Cx1) and tobramycin.

 In such a composition according to the invention, the calixarene represented by formula II (Cx1) and a given antibiotic can be physically mixed together in a final unit product.

 The calixarene represented by the formula II (Cx1) and such a given antibiotic may also be present in the form of the same final unit product, but physically separated. For example, the Cx1 and the given antibiotic may be present in two separate compartments of a capsule, respectively.

Another aspect of the invention relates to a product as described above for its use as a medicament in the treatment of pathologies involving a bacterial strain having resistance to at least one determined antibiotic.

In one advantageous embodiment, the invention relates to a product as described above for its use in the treatment of pathologies involving a resistant bacterial strain among Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, more particularly a selected resistant bacterial strain. among:

 a strain of Staphylococcus aureus of wild phenotype

 a strain of Meticillin Resistant Staphylococcus aureus (MRSA) without associated resistance,

 a strain of MRSA with resistance to aminoglycosides and fluoroquino lones,

 - a strain of MRSA with resistance to aminoglycosides, fluoroquino lones, macrolide-lincosamides-synergystins and ofloxacin,

a strain of Escherichia coli of wild phenotype

 a strain of Escherichia coli producing penicillinase without associated resistance,

a strain of Escherichia coli producing ESBL (Extended Spectrum Beta-Lactamase), exhibiting a resistance associated with aminoglycosides, with rifampicin and with the trimethoprim-sulphamethoxazole combination, a hyperproductive Escherichia coli strain of cephalosporinase, exhibiting a resistance associated with aminoglycosides, quinolones and the trimethoprim-sulfamethoxazole combination,

 - a strain of Pseudomonas aeruginosa of wild phenotype

 a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams, to trimethoprim-sulfamethoxazole and to fosfomycin,

 a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin;

 a mucosal strain of Pseudomonas aeruginosa exhibiting resistance to rifampicin and to the trimethoprim-sulfamethoxazole combination.

The product according to the invention is especially used in the treatment of pathologies involving a strain of bacteria with resistance, including nosocomial and / or community infections, such as abdominal infections, digestive infections, urinary tract infections, respiratory infections, neuro-meningeal infections, oropharyngeal infections, genital infections, endocarditis, skin and soft tissue infections, osteoarticular infections, ocular infections, septicemia or bacteremia, particularly in treatment of the pathologies listed below in Table 1.

abdominal infections peritonitis, appendicitis ...

digestive infections diarrhea common food poisoning, post-antibiotic diarrhea ...

urinary infections cystitis, pyelonephritis, prostatitis ...

respiratory infections bronchitis, pneumonia, pneumopathies, abscesses ...

neuro-meningeal infections bacterial meningitis, cerebral abscess ...

infections of the oros sinusitis sphere, otitis, tonsillitis, phlegmons, epiglottitis ...

pharyngeal

genital infections vulvitis, vaginitis / vaginosis, cervicitis, salpingitis ...

skin infections and furunculosis, abscess, eschar, diabetic foot ...

soft tissues

eye infections conjunctivitis, keratitis, endophthalmitis ... other infections septicemia or bacteremia ...

 Table 1

In a particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from tigecycline, fusidic acid or fosfomycin for its use in the treatment of pathologies involving the MRSA strain without associated resistance. In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from penicillin G, tigecycline, fusidic acid or fosfomycin for its use in the treatment of pathologies involving the MRSA strain exhibiting resistance to aminoglycosides and fluoroquinolones.

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from penicillin G, imipenem, gentamicin, tigecycline, fusidic acid or fosfomycin for its use in the treatment of pathologies involving the MRSA strain exhibiting resistance to macro-lides, to fluoroquinolones, macrolide-lincosamides-synergistines and ofloxacin.

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

a given antibiotic chosen from tigecycline, fusidic acid or fosfomycin for its use in the treatment of pathologies involving the wild-type Staphylococcus aureus strain. The term "a strain of Staphylococcus aureus wild type", a strain of Staphylococcus aureus that does not have mechanisms of acquired resistance to antibiotics (only natural resistance). In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from cefotaxime, gentamicin or rifampicin for its use in the treatment of pathologies involving the ESBL-producing Escherichia coli strain with resistance associated with aminoglycosides, rifampicin and trimethoprim-sulfamethoxazole combination .

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from gentamicin or rifampicin for its use in the treatment of pathologies involving the penicillinase-producing Escherichia coli strain without associated resistance, or the hyperproductive Escherichia coli strain of cephalosporinase exhibiting aminoglycoside-associated resistance, quinolones and the trimethoprim-sulfamethoxazole combination.

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from gentamicin, tobramycin, or rifampicin its use in the treatment of pathologies involving a strain of Escherichia coli of wild type.

"Escherichia coli strain of wild phenotype" is understood to mean a strain of E. coli. coli that does not have acquired resistance mechanisms to antibiotics (only natural resistance).

In another particularly advantageous embodiment, the invention relates to a product comprising: a calixarene represented by formula II, and

 a given antibiotic chosen from piperacillin-tazobactam, rifampicin, tobramycin for its use in the treatment of pathologies involving a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactam antibiotics, trimethoprim-sulfamethoxazole and fosfomycin.

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from ceftazidime, rifampicin, colimycin, fosfomycin for its use in the treatment of pathologies involving a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams (including carbapenems), to aminoglycosides, to trimethoprim-sulfamethoxazole combination and ciprofloxacin.

In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

 a given antibiotic chosen from piperacillin-tazobactam, imipenem, rifampicin, colimycin, fosfomycin, tobramycin and ciprofloxacin for use in the treatment of pathologies involving a mucosal strain of Pseudomonas aeruginosa exhibiting resistance to rifampicin and the trimethoprim-sulfamethoxazole combination. In another particularly advantageous embodiment, the invention relates to a product comprising:

 a calixarene represented by formula II, and

a given antibiotic chosen from piperacillin-tazobactam, ceftazidime, tobramycin, ciprofloxacin, rifampicin, fosfomycin or ticarcillin-clavulanic acid for its use in the treatment of pathologies involving a strain of Pseudomonas aeruginosa of wild type. The term "a strain of Pseudomonas aeruginosa wild type", a strain of P. aeruginosa that does not have mechanisms of acquired resistance to antibiotics (only natural resistance).

 The present invention also relates to a pharmaceutical composition comprising at least one product as described above as an active substance in combination with a pharmaceutically acceptable vehicle.

 Various formulations are possible for said pharmaceutical compositions: in capsule, tablet, powder, cream, lotion, aqueous or hydro-alcoholic solution, mouthwash, eye drops, milk, foam, gel, spray or powder, for example.

 The said pharmaceutical composition may be administered orally, parenterally, or topically.

 In one such pharmaceutical composition according to the invention, one skilled in the art knows that the unit administration dose of Cx1 depends on the nature of the bacteria to be treated, but also on the unit dose of a given antibiotic.

 The unit dosage of a given conventional antibiotic is known to those skilled in the art.

Another aspect of the present invention is to provide a combination product for simultaneous, separate or spread over time in therapy of pathologies involving at least one bacterial strain exhibiting resistance.

 Said combination product contains:

 a given antibiotic chosen from: β-lactams, aminoglycosides, fluoroquinolones, fosfomycin, colimycin, rifampicin, tigecycline, or fusidic acid, and

 a calixarene represented by the following formula I:

Formula I

dans laquelle (i) n = un entier de 4 à 16,

in which (i) n = an integer of 4 to 16,

 (ii) m = an integer of 1 to 10,

 (iii) X is selected from:

 a hydrogen,

 an alkyl group, the number of carbons being from 1 to 20, in particular from 1 to 10,

a halogen chosen from Cl, Br, I, or

an amphiphilic group chosen from an anionic group, such as the carboxylates -RC0 ₂ ^~ , the sulphates -RSO ₄ ^" , the sulphonates -RSO ₃ ^" , a cationic group, such as RNH ₃ ⁺ , in which R is an alkyl group the number of carbons being from 1 to 20, in particular from 1 to 10,

as a combination product, for simultaneous, separate or spread over time for the treatment of pathologies involving at least one bacterial strain having an acquired resistance to at least one specific antibiotic, such as abdominal infections, digestive infections, infections urinary tract infections, respiratory infections, neuro-meningeal infections, oropharyngeal infections, genital infections, endocarditis, skin and soft tissue infections, osteo-articular infections, eye infections, septicemia or bacteremia, more particularly the pathologies mentioned above in Table 1.

 In such a combination product according to the invention, the calixarene represented by formula I and the given antibiotic are physically present in a final product. The calixarene and the given antibiotic can be administered to patients simultaneously, separately or in an order spread over time, according to the prescription.

 In a particular embodiment, the invention relates to a combination product for its use as described above, wherein the calixarene corresponds to the calixarene represented by the following formula II:

Formula II

La molécule représentée par la formule II est le para-guanidinoéthylcalix[4]rène, désigné par Cxi dans la présente demande.

The molecule represented by formula II is para-guanidinoethylcalix [4] rene, designated Cxi in the present application.

In another advantageous embodiment of the combination product of the invention for its use as described above, the given antibiotic is chosen from imipenem, piperacillin-tazobactam, penicillin G, cefotaxime, ceftazidime, tobramycin, gentamicin, ciprofloxacin, rifampicin, fosfomycin, colimycin, streptomycin, ticarcillin-clavulanic acid, tigecycline or fusidic acid. In another particular embodiment, the invention relates to a combination product for simultaneous, separate or spread over time in therapy of pathologies involving at least one resistant bacterial strain belonging to a species selected from Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. In another particular embodiment, the combination product according to the invention is intended for simultaneous, separate or spread over time in therapy of pathologies involving at least one resistant bacterial strain chosen from:

 a strain of Staphylococcus aureus of wild phenotype

 a strain of Meticillin Resistant Staphylococcus aureus (MRSA) without associated resistance,

 a strain of MRSA with resistance to aminoglycosides and fluoroquino lones,

 - a strain of MRSA with resistance to aminoglycosides, fluoroquino lones, macro-lincosamides-synergystins and ofloxacin, - a strain of wild-type Escherichia coli

 a strain of Escherichia coli producing penicillinase without associated resistance,

a strain of Escherichia coli producing ESBL (Extended Spectrum Beta-Lactamase), exhibiting a resistance associated with aminoglycosides, with rifampicin and with the trimethoprim-sulphamethoxazole combination,

 a hyperproducing cephalosporinase Escherichia coli strain exhibiting a resistance associated with aminoglycosides, quino lones and the trimethoprim-sulfamethoxazole combination,

- a strain of Pseudomonas aeruginosa of wild phenotype a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams, to trimethoprim-sulfamethoxazole and to fosfomycin,

 a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin;

 a mucosal strain of Pseudomonas aeruginosa exhibiting resistance to rifampicin and to the trimethoprim-sulfamethoxazole combination.

In a particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from tigecycline, fusidic acid or fosfomycin, as a combination product, for simultaneous use, separated or spread over time in pathology therapy involving the MRSA strain without associated resistance.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from penicillin G, tigéncyline, fusidic acid or fosfomycin, as a combination product for a simultaneous, separate or spread over time in therapy of pathologies involving the MRSA strain exhibiting resistance to aminoglycosides and fluoroquinolones.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from penicillin G, imipenem, gentamicin, tigecycline, fusidic acid or fosfomycin , as a combination product for its simultaneous, separate or spread over time in therapy of pathologies involving the MRSA strain exhibiting resistance to auxaminosides, fluoroquinolones, macrolide-lincosamides-synergistines and ofloxacin.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from tigecycline, fusidic acid or fosfomycin, as a combination product for its simultaneous, separate use. or spread over time in pathology therapy involving the wild-type Staphylococcus aureus strain.

In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from the group consisting of cefotaxime, gentamicin or rifampicin, as a combination product for its simultaneous, separate or time-course use in therapy of pathologies involving ESBL-producing Escherichia coli strain with resistance associated with aminoglycosides, rifampicin and rifampicin. trimethoprim-sulfamethoxazole combination.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from gentamicin or rifampicin, as a combination product for its simultaneous, separate or spread use over time in pathology therapy involving the penicillinase-producing Escherichia coli strain without associated resistance, or the hyperproductive Escherichia coli strain of cephalosporinase exhibiting resistance associated with aminoglycosides, quinolones and the trimethoprim-sulfamethoxazole combination.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from gentamicin, tobramycin, or rifampicin, as a combination product, for its simultaneous, separate use. or spread over time in disease therapy involving the wild-type Escherichia coli strain.

In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic chosen from piperacillin-tazobactam, rifampicin, tobramycin, as combination product, for its simultaneous use, separated or spread over time in pathology therapy involving a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams, trimethoprim-sulfamethoxazole and fosfomycin.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from ceftazidime, rifampicin, colimycin, fosfomycin for its simultaneous use, separated or spread in the time in pathology therapy involving a Pseudomonas aeruginosa strain exhibiting resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin.

In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from piperacillin-tazobactam, imipenem, rifampicin, colimycin, fosfomycin, tobramycin and ciprofloxacin, as a combination product, for its use simultaneous, separate or spread over time in therapy of pathologies involving a mucosal strain of Pseudomonas aeruginosa exhibiting resistance to rifampicin and trimethoprim-sulfamethoxazole combination.

 In another particular embodiment, the invention relates to a product containing the calixarene of formula II (Cxi) and a given antibiotic selected from piperacillin-tazobactam, ceftazidime, tobramycin, ciprofloxacin, rifampicin, fosfomycin or ticarcillin-clavulanic acid, as a combination product, for its simultaneous, separate or spread over time in therapy of pathologies involving a strain of Pseudomonas aeruginosa wild type.

The figures and examples below to illustrate by way of example the present invention, can not be interpreted in any case the limitation of the scope of the invention.

figures

Figure 1: Figure 1 shows a microplate prepared to measure the sensitivity of a bacterial strain to a solution containing an antibiotic and Cxi respectively in a proportion of the determined concentrations. Columns 1 and 12 contain only control medium. Columns 2 and 11 contain control media and bacteria, but no antibiotics or Cxi. Columns 3 to 10 contain the bacteria, the Cxi in decreasing concentration and an antibiotic in increasing concentration.

Figure 2A: Figure 2A illustrates an additivity between Cxi and another antibiotic.

Figure 2B: Figure 2B illustrates an indifference between the Cxi and another antibiotic.

Figure 2C: Figure 2C illustrates a synergy between Cxi and another antibiotic.

Figure 2D: Figure 2D illustrates an antagonism between the Cxi and another antibiotic.

1. Material and Method

 1.1 Hardware and reagent

 - 10, 20 or 50 mL syringe

 0.22 μιη filter (Millex®GP filters, 0.22 μm, Millipore, France)

 - Falcon 15 and 50 mL tubes

 - 96-well plates (Greiner, 650161)

 - Mueller Hinton Agar (MHA) (Difco, 225250)

- Mueller Hinton Broths (MHB) (Difco, 275730) - Sterile distilled water

 Solution of the test drug: Cxi (M = 1221.11 g / mol) provided by Prof. Regnouf de Vains in the form of a white powder, taken up in sterile distilled water and filtered through 0.22 μιη to obtain a sterile solution with 10-2 mol / L. We procured the commercial antibiotics from the manufacturers, as a sterile powder, ready for use.

1.2 Bacterial strains

 Three reference strains were used, corresponding to those studied for MICs and CMBs (Minimal Bactericidal Concentration): Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853. For each of these strains, 3 clinical isolates were chosen. corresponding, presenting various antibiotic resistance profiles conventionally used in routine:

 EcPv1, EcR2, EcR3;

 SaR1, SaR3, SaR4;

 - PaR2, PaR3, PaR5.

 The antibiotic sensitivity profiles of these clinical isolates are shown in Appendix 1.

The fluctuations in the type of resistance associated with certain strains are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

1.3. Operating mode: Chessboard technique

 J-1: Culture of the bacteria on agar MHA (Mueller Hinton Agar)

 Incubate for 24 h at 35 ° C.

D0: Inoculation of MHB broth (Mueller Hinton Broth)

 Collect an "average" colony on J-1 agar and inoculate 5 mL of broth

MHB.

Incubate for 24 h at 35 ° C. Jl: Preparation of 96-well plates

 Preparation of the bacterial inoculum:

 The purity of the strains is verified by the absence of contaminants on the MHA agar seeded parallel to the broth, and by carrying out a Gram stain.

The bacterial suspension is transferred into a 15 ml Falcon tube, centrifuged for 10 min at 4500 g and then the pellet is resuspended in 1 ml of sterile distilled water. The appropriate dilutions are then carried out in order to obtain a bacterial inoculum between 5.10 ⁵ and 5.10 ⁶ CFU / mL.

Prepare the solutions: 1) Antibiotic (ATB) to test, 2) Cxi

 Antibiotic MICs were determined for each strain, by CLSI (Clinical and Laboratory Standards Institute), 2003].

 The appropriate dilutions are carried out in order to obtain a concentration solution equivalent to 32 times the MIC of ΓΑΤΒ to be tested, in MH medium (Mueller-Hinton). Then we proceeded to a series of second order dilutions in MH medium in order to obtain the following concentrations: 16, 8, 4, 2, 1, 0.5 and 0.25 times the MIC (15 mL Falcon tubes ). The same procedure is followed for Cxi. This makes it possible to obtain a concentration range of 8 to 0.06 times the MIC in the microplate for the two molecules (half dilution with the addition of the second molecule, then a new dilution at ½ after addition of the bacterial suspension). This gives 64 ATB / Cx1 combinations.

 For each plate, 1 mL of solution of each dilution is required.

Preparation of microplates

 The final volume contained in each of the wells must be 100 μί. Two witnesses must be present on each plate:

 - Columns 1 and 12: middle control

 - column 2 and 11: control medium + bacteria Distribution of medium MH

 100 in each of the wells in columns 1 and 12.

50 in each of the wells in columns 2 and 11. Distribution of the dilution range of the antibiotic to be tested and the molecule of interest

 Cxi: 25 μΐ, in the wells of columns 11 to 3, starting with the lowest concentration.

 ATB: 25 in the wells of rows H to A (columns 3 to 11), starting with the lowest concentration.

Distribution of the bacterial suspension

 50 in each of the wells of columns 2 to 11.

J2: Turbidity reading at 540 nm.

 The different types of interactions observed by the chessboard technique are presented in FIGS. 2A, 2B, 2C and 2D: The Fractional Inhibitory Concentration Index (FIC) is determined by the following formula:

Fc = Fc _A + FfC ₈ = C¾ in assoe + CMin & n assoe

_CMT alone MIC _B SEUF When FIC <0.5, there is a synergistic effect between the antibiotic and the antibiotic A B.

When 0.5 <FIC <1, there is an additive effect between antibiotic A and antibiotic B. When 1 <FIC <4, there is an indifferent effect between antibiotic A and antibiotic

B.

 When FIC> 4, there is an antagonistic effect between antibiotic A and antibiotic B. For each strain and each antibiotic / Cx1 combination, the experiments were repeated at least 3 times.

2. Results & Discussion

 The results obtained are presented in tabular form (Tables I to XII), presenting in more detail, by ATB / Cx1 couple:

 - the index FICs obtained during the different experiments;

- optimal concentrations for synergy; the MICs of the compounds used alone;

 - the evaluated ranges and nature of the observed interaction.

The results below show that no antagonism between the Cxi and an antibiotic tested was observed, regardless of the strain and associations tested.

 The results also demonstrate that treatment with Cxi in combination with antibiotic treatment for a pathology involving a bacterial strain exhibiting resistance to said antibiotic allows:

 to confer a certain level of sensitivity of the bacterial strain with respect to said antibiotic;

 to reduce the dose of said antibiotic and the dose of Cxi administered.

 The results demonstrate that the treatment with Cxi in combination with the treatment with an antibiotic for a pathology involving a bacterial strain having a resistance to a given antibiotic can reduce the dose of antibiotic and the dose of Cxi administered.

 These results are also valid for the treatment with Cxi in combination with the treatment with an antibiotic for a pathology involving a bacterial strain having resistance to at least two families of different antibiotics. This is the case of the SaR3, AcR1, SaR4, PaR2 and PaR3 strains tested.

Pseudomonas aeruginosa is the strain, among all the strains analyzed, on which the greatest number of synergistic associations, with very varied antibiotics (β-lactams, aminoglycosides, fluoroquinolones ...), was observed.

 In addition, the antibiotics for which a synergy between which and the Cxi has been observed act at:

 - the wall: fosfomycin (knowing that the specific mechanism of action of fosfomycin results in an almost constant synergy of action with other antibiotics active on the bacterial wall) but also with the piperacillin-tazobactam and ticarcillin- clavulanic acid, and ceftazidime;

 protein synthesis: tigecycline, gentamicin, tobramycin, streptomycin, fusidic acid;

- the synthesis of nucleic acids: rifampicin, ciprofloxacin Synergy of the association of Cxl with antibiotics against strains (V Escherichia coli resistant or non-resistant to antibiotics) 2.1 Table I: Synergy with the strain escherichia coli ATCC 25922 (wild type) ( n = 4)

2.2. Table II: Synergy against a penicillinase-producing Escherichia coli strain without associated resistance (or EcR1

2.3. Table III: Synergy against a ESBL-producing Escherichia coli strain with aminoglycoside-associated resistance (or EcR3) (n = 4)

2.4. Table IV: Synergy against a hyperproductive Escherichia coli strain of cephalosporinase showing resistance associated with aminoglycosides, quinolones and trimethoprim-sulfamethoxazole (or EcR2) combination (n = 4)

3. Synergy of the association of Cxl with antibiotics against strains of Staphylococcus aureus resistant or not to antibiotics

 3.1. Table V: Synergy against Staphylococcus aureus strain ATCC 29213 (wild type) (n = 4)

3.2. Table VI: Synergy against a MRSA strain without associated resistance (or SaR1) (n = 4)

. Table VII: Synergy against a MRSA strain with aminoglycoside and fluoroquinolone resistance n = 4)

3.4. Table VIII: Synergy against a MRSA strain showing resistance to aminoglycosides, fluoroquinolones, macrolide-lincosamides-synergistins and ofloxacin (SaR4) (n = 4)

4. Synergy of the association of Cxl with antibiotics against strains of Pseudomonas aeruginosa resistant or not to antibiotics

 4.1. Table IX: Synergy against Pseudomonas aeruginosa strain ATCC 27853 (wild type) (n = 4)

4.2. Table X: Synergy against a Vseudomonas aeruginosa strain exhibiting β-lactam resistance, trimethoprim-sulfamethoxazole and fosfomycin (or PaR2) combination (n = 4)

4.3. Table XI: Synergy against a strain of Pseudomonas aeruginosa showing resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin (or PaR3) (n = 4)

4.4. Table XII: Synergy against a mucosal strain of Pseudomonas aeruginosa with resistance to rifampicin and trimethoprim-sulfamethoxazole (or PaR5) (n = 4)

5. Identification and antibiograms. l ECRI: Escherichia coli producing penicillinase without associated resistance

 Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique.

 Al Table

 dmin

 Antibiotic Diameter Results CMI mg / L Results

 Dmax

 Amoxicillin 6 14-21 Resistant> 32 Resistant

Amox + ac.clavulanic 20 14-21 Intermediate 4 Sensitive

Ticarcillin 6 18-22 Resistant> 128 Resistant

Piperacillin 17 12-20 Intermediate <8 Sensitive

Piper + tazobactam 25 14-21 Sensitive <4 Sensitive

C1G 17 12-18 Intermediate 4 Sensitive

Cefoxitin 24 15-22 Sensitive <4 Sensitive

Cefotaxime 30 15-21 Sensitive <1 Sensitive

Ceftazidime <1 Sensible

Imipenem <1 Sensible

Aztreonam 28 17-23 Sensitive

 Tobramycin 19 14-16 Sensitive <1 Sensitive

Gentamicin 20 14-16 Sensitive <1 Sensitive

Amikacin 19 15-17 Sensitive <2 Sensitive

Netilmicine 24 17-19 Sensitive <1 Sensitive

Minocycline 20 17-19 Sensible

 Colistine 15 15 Sensitive

 Trimethoprim -

21 10-16 Sensitive <20 Sensitive Sulfamet.

 Nalidixic acid <2 Sensible

Norfloxacin <0.5 Sensitive

Ofloxacin <0.25 Sensitive

Pefloxacin 26 16-22 Sensitive

 Ciprofloxacin 27 19-22 Sensitive <0.25 Sensitive

Rifampicin 16 14-19 Intermediate

 Fosfomycin 24 14 Sensitive

 Nitro furantoin <16 Sensible

Cefepime 27 15-21 Sensitive

Table A2

 This CA-

MIC mg / L

 SFM Interpretation Interpretation Antibiotics (diameter

2011 CA-SFM CLSI in mm) _™ , EUCAST

 mg / L

 Amoxicillin> 32 4-8 Resistant 8 Resistant 8-32 Resistant

Amox +

 4-8 Sensitive 8 Sensitive 8-32 Sensitive ac.clavulanic

 16-

Ticarcillin> 128 8-16 Resistant 8-16 Resistant Resistant

 128

Piperacillin <8 8-16 Sensitive 8-16 Sensitive 16- Sensitive 128

Piper + 16-

<4 8-16 Sensitive 8-16 Sensitive Sensitive tazobactam 128

 Cefalotin 4 8-32 Sensitive 16 Sensitive 8-32 Sensitive

Cefoxitin <4 8-32 Sensitive NA - 8-32 Sensitive

Cefotaxime <1 1-2 Sensitive 1-2 Sensitive 1-4 Sensitive

Ceftazidime <1 1-4 Sensitive 1-4 Sensitive 4-16 Sensitive

 14-

Cefepime 27 24 Sensitive 21-24 Sensitive Sensitive

 18

 Imipenem <0.5 0.5-1 Sensitive 2-8 Sensitive 4-16 Sensitive

 17-

Aztreonam 28 21-27 Sensitive 24-27 Sensitive Sensitive

 21

 Tobramycin <1 2-4 Sensitive 2-4 Sensitive 4-16 Sensitive

Gentamicin <1 2-4 Sensitive 2-4 Sensitive 4-16 Sensitive

 16-

Amikacin <2 8-16 Sensitive 8-16 Sensitive Sensitive

 64

 Netilmicin <1 2-4 Sensitive 2-4 Sensitive 8-32 Sensitive

 12-

Minocycline 20 17-19 Sensible - - Sensible

 16

 Colistine 15 15 Sensitive 17 Resistant n / a n / a

Trimethoprim -

<20 2-4 Sensitive 2-4 Sensitive 2-4 Sensitive Sulfamate.

 16-

Nalidixic acid <2 8-16 Sensitive NA - Sensitive

 32

 Norfloxacin ≤0.5 0.5-1 Sensitive 0.5-1 Sensitive 4-16 Sensitive

Ofloxacin <0.25 0.5-1 Sensitive 0.5-1 Sensitive 2-8 Sensitive

Ciprofloxacin <0.25 0.5-1 Sensitive - - 1-4 Sensitive

Rifampicin 16 14-19 Intermediate - - n / a

 12-

Fosfomycin 24 14 Sensitive - - Sensitive

 16

 32-

Nitrofurantoin <16 64 Sensitive 64 Sensitive Sensitive

 128

 * Cc: Critical Concentration

 Expert conclusion July 2006: Acquired Penicillinase

The fluctuations in the type of resistance associated with certain strains between Tables A1 and A2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations in terms of categorization of bacterial strains.

5.2 EcR2: Escherichia coli hyperproductive cephalosporinase with resistance associated with aminoglycosides, quinolones and trimethoprim-sulfamethoxazole

 Bacterial identification and antibiogram is performed by the VITEK1 system

(bioMérieux) and the disk diffusion technique

 Table Bl

 dmin

 Antibiotic Diameter Results CMI mg / L

 Dmax

 Amoxicillin Resistant> 32

 Amox + ac.clavulanic Resistant> 32

 Ticarcillin Intermediate 32

 C1G Resistant> 64

 Cefoxitin 11 15-22 Resistant

 Cefotaxime 24 15-21 Intermediate

 Ceftazidime 20 15-21 Intermediate

 Sensitive Imipenem <4

 Tobramycin 10 16-18 Resistant

 Gentamicin 12 16-18 Resistant

 Netilmicin 21 19-21 Sensitive <1

 Trimethoprim - Sulfamet. Intermediate 160

 Nalidixic acid Resistant> 32

 Pefloxacin Resistant> 8

 Nitrofurantoin Sensitive <25

Table B2

 Cc * CA

MIC mg / L, ₄ Ce Ce

.. . , .., -SFM Interpretation Interpretation Interpretatio

Anfb.ot.ques (d.ameter EUCAST CLSI

 EUCAST n CLSI in mm) "2011 2011

 mg / L

 Amoxicillin> 32 4-8 Resistant 8 Resistant 8-32 Resistant

Amox +

 > 32 4-8 Resistant 8 Resistant 8-32 Resistant ac.clavulanic

 16-

Ticarcillin 32 8-16 Resistant 8-16 Resistant Resistant

 128

 Cefalotine> 64 8-32 Resistant 16 Resistant 8-32 Resistant

Cefoxitin 11 15-22 Resistant 19 Resistant 14-18 Resistant

** Cefotaxime 24 23-26 Intermediate 18-21 Resistant 22-26 Intermediate

** Ceftazidime 20 23-26 Resistant 19-22 Intermediate 17-21 Intermediate

Imipenem <0.5 0.5-1 Sensitive 2-8 Sensitive 4-16 Sensitive

Tobramycin 10 16-18 Resistant 13-16 Resistant 12-15 Resistant

* * Gentamicin 12 16-18 Resistant 14-17 Resistant 12-15 Resistant

Netilmicin <1 2-4 Sensitive 2-4 Sensitive 8-32 Sensitive

Trimethoprim -

160 2-4 Resistant 2-4 Resistant 8-16 Sulfamate Resistant.

 Acid

 > 32 8-16 Resistant - - 16-32 Nalidixic Resistant

 Pefloxacin> 8 1-4 Resistant - - -

32-

Nitrofurantoin <25 64 Sensitive 64 Sensitive Sensitive

128 * Cc: Critical Concentration

 ** Attention: The disk load is different between CA-SFM and EUCAST; Γ interpretation of EUCAST is therefore not applicable in this case. In addition, the technique of performing the disk diffusion test is different in the two reference systems.

The fluctuations in the type of resistance associated with certain strains between Tables B1 and B2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.3 EcR3: Escherichia coli producing ESBL with resistance associated with aminoglycosides, rifampicin and trimethoprim-sulfamethoxazole

Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique

 Table Cl

 dmin

 Antibiotics Diameter Results

 Dmax

 Amoxicillin 6 14-21 Resistant

Amox + ac.clavulanic 16 14-21 Intermediate

Ticarcillin 6 18-22 Resistant

Piperacillin 13 12-20 Intermediate

Piper + tazobactam Intermediate

C1G 6 12-18 Resistant

Cefoxitin Intermediate

Cefotaxime 19 15-21 Intermediate

Imipenem 27 17-22 Sensitive

 Tobramycin 6 14-16 Resistant

Gentamicin 12 14-16 Resistant

Amikacin 17 15-17 Sensitive

 Netilmicin 10 17-19 Resistant

Minocycline 21 17-19 Sensible

 Colistine 16 15 Sensitive

 Trimethoprim - Sulfamet. 6 10-16 Resistant

Pefloxacin 23 16-22 Sensitive

 Ciprofloxacin 25 19-22 Sensitive

 Rifampicin 15 14-19 Intermediate

Fosfomycin 23 14 Sensitive

 Cefepime 24 15-21 Intermediate

Table C2

 From * De De

 diameter Interpretation Interpretation Interpretation

Antibiotics CA-SFM EUCAST CLSI

 in mm CA-SFM EUCAST CLSI

 2011 2011 2011

 Amoxicillin 6 16-19 Resistant 14 Resistant 13-17 Resistant

Amox +

 16 16-21 Intermediate 17 Resistant 13-18 Intermediate ac.clavulanic

 Ticarcillin 6 22-24 Resistant 22-23 Resistant 14-20 Resistant

Piperacillin 13 16-20 Resistant 15-18 Resistant 17-21 Resistant

** Piper +

 18 17-21 Intermediate 15-18 Sensitive 17-21 Intermediate tazobactam

 Cefalotine 6 12-18 Resistant - - 14-18 Resistant

Cefoxitin 6 15-22 Resistant 19 Resistant 14-18 Resistant

** Cefotaxime 19 23-26 Resistant 18-21 Intermediate 22-26 Resistant

Cefepime 24 24 Sensitive 21-24 Sensitive 14-18 Sensitive

Imipenem 27 17-24 Sensitive 15-21 Sensitive 13-16 Sensitive

Tobramycin 6 16-18 Resistant 13-16 Resistant 12-15 Resistant

** Gentamicin 12 16-18 Resistant 14-17 Resistant 12-15 Intermediate Amikacin 17 15-17 Sensitive 13-16 Sensitive 14-17 Sensitive

** Netilmicin 10 19-21 Resistant 12-15 Resistant 12-15 Resistant

Minocycline 21 17-19 Sensible - - 12-16 Sensible

Colistine 16 15 Sensitive - - - -

Trimethoprim -

6 13-16 Resistant 13-16 Resistant 10-16 Resistant Sulfamate.

 Pefloxacin 23 16-22 Sensitive - - - -

Ciprofloxacin 25 22-25 Sensitive - - 15-21 Sensitive

Rifampicin 15 14-19 Intermediate - - - -

Fosfomycin 23 14 Sensitive - - 12-16 Sensitive

* Dc: Critical diameter

 ** Attention: The disk load is different between CA-SFM and EUCAST; the interpretation of EUCAST is not applicable in the present case. In addition, the technique of performing the disk diffusion test is different in the two reference systems.

The fluctuations in the type of resistance associated with certain strains between Tables C1 and C2 are due to the evolution of the French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.4 SaRl: Staphylococcus aureus Meticillin Resistant Without Associated Resistance

 Bacterial identification and antibiogram is performed by the VITEK2 system (bioMérieux)

 Table Dl

 dmin

 Antibiotic Diameter Results CMI mg / L Results

 Dmax

 Penicillin G 28 9-29 Resistant> 0.5 Resistant

Oxacillin> 8 Resistant

Kanamycin 20 15-17 Sensitive <4 Sensitive

Tobramycin 22 14-16 Sensitive <1 Sensitive

Gentamicin 23 14-16 Sensitive <0.5 Sensitive

Chloramphenic 1 25 19-23 Sensitive

 Minocycline 27 17-19 Sensible

 Erythromycin 25 17-22 Sensitive <0.25 Sensitive

Lincomycin 24 17-21 Sensitive <1 Sensitive

Pristinamycin 25 19-22 Sensitive <0.5 Sensitive

Quinupristine-dalfopristine <0.25 Sensitive

Trimethoprim - Sulfamet. 26 10-16 Sensitive <10 Sensitive

Ofloxacin 24 16-22 Sensitive 1 Sensitive

Fusidic Acid 28 15-22 Sensitive <0.5 Sensitive

Vancomycin Sensitive <1 Sensible

Sensitive Teicoplanin <0.5 Sensitive

Rifampicin 30 14-29 Sensitive <0.5 Sensitive

Fosfomycin 40 14 Sensitive <8 Sensitive

Linézolide 29 24-28 Sensitive 2 Sensitive

Minocycline <0.5 Sensible

Nitro furantoin <16 Sensible

Table D2

 Cc * CA-

This Ce

 CMI SFM Interpretation Interpretation

 Antibiotics EUCAST CLSI Interpretation CLSI mg / L 2011 CA-SFM EUCAST

 2011 2011

 mg / L

 0,12-

Penicillin G ≥0.5 0.12 Resistant 0.125 Resistant Resistant

 0.25

 Oxacillin> 8 2 Resistant 2 Resistant 2-4 Resistant

 Kanamycin <4 8-16 Sensitive 8-16 Sensitive 16-64 Sensitive

Tobramycin <1 1 Sensitive 1 Sensitive 4-16 Sensitive

Gentamicin ≤0.5 1 Sensitive 1 Sensitive 4-16 Sensitive

 <Sensitive

Erythromycin 1-2 Sensitive 1-2 Sensitive 0.5-8

 0.25

 Lincomycin <1 2-8 Sensitive - - - -

Pristinamycin ≤0.5 1-2 Sensitive - - - -

Quinupristine- <Sensible

 1-2 Sensitive 1-2 Sensitive 1-4

 0.25 dalfopristine

 Trimethoprim - Sensitive

 <10 2-4 Sensitive 2-4 Sensitive 2-4

 Sulfamét.

 Ofloxacin 1 1 Sensitive 1 Sensitive 1-4 Sensitive

Fusidic acid ≤0.5 1 Sensitive 1 Sensitive - - Vancomycin <1 2 Sensitive 2 Sensitive 4-32 Sensitive

Teicoplanin <0.5 4 Sensitive 2 Sensitive 8-32 Sensitive

 0.06- 0.064- Sensitive

Rifampicin <0.5 Sensitive Sensitive 1-4

 0.5 0.5

 Fosfomycin <8 32 Sensitive 32 Sensitive - -

Linézolide 2 4 Sensitive 4 Sensible 4-8 Sensitive

Minocycline <0.5 0.5-1 Sensitive 0.5-1 Sensitive 4-16 Sensitive

 32- Sensitive

Nitrofurantoin <16 64 Sensitive 64 Sensitive

 128

* This: Critical Concentration

 February 2006: Research of mecA gene by PCR technique: POSITIVE

Expert conclusion July 2006: phenotype quite typical: modification of PLP

The fluctuations in the type of resistance associated with certain strains between Tables D1 and D2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.5 SaR3: Meticillin-Resistant Staphylococcus aureus with resistance to aminoglycosides and fluoroquinolines

Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique

 El Table

 Antibiotics Diameter Dmin Dmax Results

 Penicillin G 26 9-29 Resistant

oxacillin

 Kanamycin 6 15-17 Resistant

Tobramycin 6 14-16 Resistant

Gentamicin 20 14-16 Sensitive

Chloramphenic 1 6 19-23 Resistant

Minocycline 26 17-19 Sensible

Erythromycin 25 17-22 Sensitive

Lincomycin 23 17-21 Sensitive

Pristinamycin 23 19-22 Sensitive

Trimethoprim - Sulfamet. 27 10-16 Sensitive

Ofloxacin 6 16-22 Resistant

Fusidic Acid 29 15-22 Sensitive

Vancomycin Sensible

Teicoplanine Sensible

Rifampicin 31 14-29 Sensitive

Fosfomycin 26 14 Sensitive

Linézolide 26 24-28 Sensible

Table E2

 Of*

 From De

 diameter CA- Interpretation Interpretation Interpretation

Antibiotics EUCAST CLSI

 in mm SFM CA-SFM EUCAST CLSI

 2011 2011

 2011

 Penicillin G 26 Resistant 26 Resistant 28-29 Resistant

Cefoxitin 17 25-37 Resistant 22 Resistant 21-22 Resistant

** Kanamycin 6 15-17 Resistant 16-18 Resistant 13-18 Resistant

Tobramycin 6 20 Resistant 18 Resistant 12-15 Resistant

** Gentamicin 20 20 Sensitive 18 Sensitive 12-15 Sensitive

Erythromycin 25 19-22 Sensitive 18-21 Sensitive 13-23 Sensitive

Lincomycin 23 17-21 Sensitive - - - -

Pristinamycin 23 19-22 Sensitive - - - -

Trimethoprim -

27 13-16 Sensitive 14-17 Sensitive 10-16 Sensitive Sulfamate.

 Ofloxacin 6 22 Resistant 20 Resistant 14-18 Resistant

Fusidic acid 29 24 Sensitive 24 Sensitive - -

Vancomycin 28 17 Sensitive - - - -

Teicoplanine 27 17 Sensitive - - 10-14 Sensitive

Rifampicin 31 24-29 Sensitive 23-26 Sensitive 16-20 Sensitive

Fosfomycin 26 14 Sensitive - - - -

** Linézolide 26 24 Sensitive 19 Sensible 20-21 Sensitive

Minocycline 26 21-23 Sensitive 20-23 Sensitive 14-19 Sensitive * From: Critical diameter

 ** Attention: The disk load is different between CA-SFM and EUCAST; The interpretation of EUCAST is not applicable in the present case. In addition, the technique of performing the disk diffusion test is different in the two reference systems.

The fluctuations in the type of resistance associated with certain strains between Tables E1 and E2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.6 SaR4: Meticillin-Resistant Staphylococcus aureus with resistance associated with aminoglycosides, fluoroquinolones, macrolide-lincosamines-synergistins and pofloxacin

Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique

 Fl Painting

 Antibiotics Diameter Dmin Dmax Results MIC mg / L

 Penicillin G Resistant

 Oxacillin Resistant> 8

 Kanamycin 7 15-17 Resistant

 Tobramycin 6 20-20 Resistant

 Gentamicin 21 20-20 Sensitive

 Chloramphenolic 1 Sensible 8

 Tetracycline Sensitive <1

 Minocycline Sensible <4

 Erythromycin Resistant> 8

 Lincomycin Resistant> 16

 Pristinamycin Sensible <2

 Trimethoprim - Sulfamet. Sensitive <10

 Ofloxacin Resistant> 8

 Nitro furantoin Sensitive <25

 Sensitive fusidic acid <1

 Vancomycin Sensible 1

 Sensitive Teicoplanin <4

 Rifampicin Sensitive <1

 Fosfomycin Resistant> 64

Table F2

 Cc * CA-

MIC mg / L This ■ ■ This

 SFM Interpretation Interpretation Interpretation Antibiotics (EUCAST diameter

 2011 CA-SFM EUCAST CLSI in mm) 2011 2011

 mg / L

 Penicillin G 0.12-

Resistant Resistant Resistant

 0.25

 Oxacillin> 8 2 Resistant 2 Resistant 2-4 Resistant

** Kanamycin 13- Resistant

 15-17 Resistant 16-18 Resistant

 18

 Tobramycin 12- Resistant

 6 20 Resistant 18 Resistant

 15

 ** Sensitive Gentamicin

 20 Sensitive 18 Sensitive

 15

 Tetracycline <1-2 Sensitive 1-2 Sensitive 4-16 Sensitive

Minocycline <0.5 0.5-1 Sensitive 0.5-1 Sensitive 4-16 Sensitive

Erythromycin> 8 1-2 Resistant 1-2 Resistant 0.5-8 Resistant

Lincomycin> 16 2-8 Resistant - - -

Pristinamycin <2 1-2 Sensitive - - -

Trimethoprim - <10 2-4 Sensitive 2-4 Sensitive 2-4 Sensitive Sulfamét.

 Ofloxacin> 8 1 Resistant 1 Resistant 1-4 Resistant

 Nitrofurantoin 32- Sensitive

 <25 64 Sensitive 64 Sensitive

 128

 Fusidic acid <1 1 Sensitive 1 Sensitive

 Vancomycin 1 2 Sensitive 2 Sensitive 4-32 Sensitive Teicoplanin <4 4 Sensitive 2 Sensitive 8-32 Sensitive Rifampicin 0.06- 0.064- 1-4 Sensitive

 <1 Sensitive Sensitive

 0.5 0.5

 Fosfomycin> 64 32 Resistant 32 Resistant

* Cc: Critical Concentration

 ** Attention: The disk load is different between CA-SFM and EUCAST; Γ interpretation of EUCAST is therefore not applicable in the present case. In addition, the technique of performing the disk diffusion test is different in the two reference systems.

Fluctuations in the type of resistance associated with certain strains between Tables Fl and F2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.7 PaR2: Pseudomonas aeruginosa with resistance associated with β-lactams, trimethoprim-sulfamethoxazole and fosfomycin

Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique

 Gl Table

 Antibiotics Diameter Dmin-Dmax Results

 Ticar + ac. clavulanic 10 18-22 Resistant

 Ticarcillin 10 18-22 Resistant

 Piperacillin 22 12-18 Sensitive

 Piper + tazobactam 22 14-19 Sensitive

 Ceftazidime 23 15-21 Sensitive

 Aztreonam 16 17-23 Resistant

 Imipenem 27 17-22 Sensitive

 Tobramycin 24 14-16 Sensitive

 Gentamicin 21 14-16 Sensitive

 Amikacin 22 15-17 Sensitive

 Netilmicin 19 17-19 Sensible

 Minocycline 6 17-19 Resistant

 Colistine 20 15-15 Sensitive

 Trimethoprim - Sulfamet. 6 10-16 Resistant

 Pefloxacin 8 16-22 Resistant

 Rifampicin 25 19-22 Sensitive

 Fosfomycin 13 14-19 Resistant

 Ciprofloxacin 18 14-14 Sensitive

 Cefepime 19 15-21 Intermediate

Table G2

 Of*

 From De

 diameter CA- Interpretation Interpretation Interpretation

Antibiotics EUCAST CLSI

 in mm SFM CA-SFM EUCAST CLSI

 2011 2011

 2011

 Ticar + ac. 17 14-15 Resistant

 10 22 Resistant Resistant

 clavulanic

 Ticarcillin 10 22 Resistant 17 Resistant 14-15 Resistant

 ** Piperacillin 22 18 Sensitive 19 Sensitive 17-18 Sensitive

** Piper + 17-18 Sensitive

 22 19 Sensitive 19 Sensitive

 tazobactam

 ** Ceftazidime 23 19 Sensitive 16 Sensitive 14-18 Sensitive

Cefepime 19 19 Sensitive 18 Sensitive 14-18 Sensitive

Aztreonam 16 19-27 Resistant 16-50 Resistant 15-22 Intermediate

Imipenem 27 17-22 Sensitive 17-20 Sensitive 13-16 Sensitive

Tobramycin 24 16 Sensitive 16 Sensitive 12-15 Sensitive

** Gentamicin 21 16 Sensitive 15 Sensitive 12-15 Sensitive

Amikacin 22 15-17 Sensitive 15-18 Sensitive 14-17 Sensitive

** Netilmicin 19 19 Sensitive 12 Sensitive 12-15 Sensitive

Minocycline 6 - Resistant - - - -

Colistine 20 - Sensitive - - 10-11 Sensitive

Trimethoprim- 6 - Resistant 16 Resistant - - Sulfamét.

 Ciprofloxacin 25 22-25 Sensitive 22-25 Sensitive 15-21 Sensitive Rifampicin 25 14-19 Sensitive

 Fosfomycin 13 14 Resistant

 * Dc: Critical diameter

 ** Attention: The disk load is different between CA-SFM and EUCAST; Γ interpretation of EUCAST is therefore not applicable in the present case. In addition, the technique of performing the disk diffusion test is different in the two reference systems.

The fluctuations in the type of resistance associated with certain strains between Tables G1 and G2 are due to the evolution of the French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.8 PaR3: Pseudomonas aeruginosa with resistance associated with β-lactams, aminoglycosides (including carbapenems), trimethoprim-sulfamethoxazole and ciprofloxacin

Bacterial identification and antibiogram is performed by the VITEK2 system (bioMérieux)

 Table Hl

 Antibiotics CMI Results

 Ticar + ac. clavulanic> 128 Resistant

 Ticarcillin> 128 Resistant

 Piperacillin> 128 Resistant

 Piper + tazobactam> 128 Resistant

 Ceftazidime 4 Sensible

 Aztreonam 16 Sensible

 Imipenem ≥ 16 Resistant

 Meropenem ≥ 16 Resistant

 Tobramycin ≥ 16 Resistant

 Gentamicin ≥ 16 Resistant

 Sensitive Amikacin 4

 Minocycline 4 Resistant

 Colistin ≤0.5 Sensitive

 Trimethoprim - Sulfamet. ≥320 Resistant

 Pefloxacin 4 Intermediate

Sensitive Ciprofloxacin 1

 Cefepime 16 Intermediate

Table H2

 Cc * CA-

This Ce

 CMI SFM Interpretation Interpretation Interpretation

Antibiotics EUCAST CLSI

 mg / L 2011 CA-SFM EUCAST CLSI

 2011 2011

 mg / L

 Ticar + ac. 64-

> 128 16 Resistant 16 Resistant Resistant Clavulanic 128

 64-

Ticarcillin> 128 16 Resistant 16 Resistant Resistant

 128

 64-

Piperacillin> 128 16 Resistant 16 Resistant Resistant

 128

 Piper + 64-

> 128 16 Resistant 16 Resistant Resistant tazobactam 128

 Ceftazidime 4 8 Sensitive 8 Sensitive 8-32 Sensitive

Cefepime 16 8 Resistant 8 Resistant 8-32 Intermediate

Aztreonam 16 1-16 Resistant 1-16 Resistant 8-32 Intermediate

Imipenem> 16 4-8 Resistant 4-8 Resistant 4-16 Resistant

 Meropenem> 16 2-8 Resistant 2-8 Resistant 4-16 Resistant

 Tobramycin> 16 4 Resistant 4 Resistant 4-16 Resistant

 Gentamicin> 16 4 Resistant 4 Resistant 4-16 Resistant

Amikacin 4 8-16 Sensitive 8-16 Sensitive 16-64 Sensitive Minocycline 4 - Resistant

 Colistine <0.5 2-4 Sensitive 4 SSeennssiibbllee 2-8 Sensitive Trimethoprim

 > 320 Resistant Resistant

 - Sulfamét.

 Ciprofloxacin 1 0.5-1 Intermediate 0.5-1 Intermediate 1-4 Sensitive

* Cc: critical concentration

The fluctuations in the type of resistance associated with certain strains between Tables H1 and H2 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

5.9 PaR5: Pseudomonas aeruginosa with resistance associated with rifampicin and trimethoprim-sulfamethoxazole

Bacterial and antibiogram identification is performed by the VITEK2 system (bioMérieux) and the disk diffusion technique

 Table II

 Antibiotics Diameter Dmin-Dmax Results

 Ticar + ac. clavulanic 40 18-22 Sensitive

 Ticarcillin 32 18-22 Sensible

 Piperacillin 33 12-18 Sensitive

 Piper + tazobactam 40 14-19 Sensible

 Ceftazidime 32 15-21 Sensitive

 Aztreonam 33 17-23 Sensible

 Imipenem 25 17-22 Sensitive

 Meropenem 34 15-20 Sensible

 Tobramycin 28 14-16 Sensitive

 Gentamicin 25 14-16 Sensitive

 Amikacin 27 15-17 Sensitive

 Netilmicin 28 17-19 Sensible

 Minocycline 11 17-19 Resistant

 Colistine 23 15 Sensitive

 Trimethoprim - Sulfamet. 6 10-16 Resistant

 Norofloxacin 17 22-25 Resistant

 Ofloxacin 11 22-25 Resistant

 Ciprofloxacin 30 19-22 Sensitive

 Rifampicin 13 14-19 Resistant

 Fosfomycin 30 14 Sensitive

 Cefepime 32 15-21 Sensitive

Table 12

 Of*

 Of

diameter CA- Interpretation _{cl IRA} _ _T Interpretation From CLSI Interpretation

antibiotics

in mm SFM CA-SFM " _Λ ""EUCAST 2011 CLSI

 2011

 2011

 Ticar + ac. 17 Sensitive

 40 22 Sensitive Sensitive 14-15

 clavulanic

 Ticarcilline 32 22 Sensitive 17 Sensitive 14-15 Sensitive

** Piperacillin 33 18 Sensitive 19 Sensitive 17-18 Sensitive

 ** Piper + Sensible

 40 19 Sensitive 19 Sensitive 17-18

 tazobactam

 ** Ceftazidime 32 19 Sensitive 16 Sensitive 14-18 Sensitive

 Cefepime 32 19 Sensitive 18 Sensitive 14-18 Sensitive

Aztreonam 33 19-27 Sensitive 16-50 Intermediate 15-22 Sensitive

Imipenem 25 17-22 Sensitive 17-20 Sensitive 13-16 Sensitive

Meropenem 34 15-22 Sensitive 18-24 Sensitive 13-16 Sensitive

Tobramycin 28 16 Sensitive 16 Sensitive 12-15 Sensitive

** Gentamicin 25 16 Sensitive 15 Sensitive 12-15 Sensitive

Amikacin 27 15-17 Sensitive 15-18 Sensitive 14-17 Sensitive ** Netilmicin 28 19 Sensitive 12 Sensitive 12-15 Sensitive

 Minocycline 11 - Resistant - - - -

Colistine 23 - Sensitive - - 10-11 Sensitive

Trimethoprim 16 Resistant

 6 - Resistant - - - Sulfamet.

 Ciprofloxacin 30 22-25 Sensitive 22-25 Sensitive 15-21 Sensitive

Rifampicin 13 14-19 Resistant - - - -

Fosfomycin 30 14 Sensitive - - - -

* Dc: critical diameter

 ** Attention: The disk load is different between CA-SFM and EUCAST; Γ interpretation of EUCAST is therefore not applicable in the present case. In addition, the technique for performing the disk diffusion test is different in the two reference systems.

The fluctuations in the type of resistance associated with certain strains between Tables II and 12 are due to the evolution of French (CA-SFM), European (EUCAST) and American (CLSI) recommendations for the categorization of bacterial strains.

 6. Synergy of the association of Cxi with antiseptics vis-à-vis bacterial strains of wild phenotype

 6.1. Synergy vis-à-vis the strain of E. ATCC 25922 (wild type)

6.2 Synergism with S. aureus strain ATCC 29213 (wild type)

6.3. Synergism with P. aeruginosa strain ATCC 27853 (wild type)

 CMI CMI ranges

 FIC Difference Difference

 Initial associations tested optimal Conclusion CMI Cxi CMI ATS index

(mg / L) (mg / L) (mg / L)

Claims

1. Product comprising at least one given antibiotic and a calixarene represented by the following formula I: Formula I

in which :  (i) n = an integer of 4 to 16,  (ii) m = an integer of 1 to 10,  (iii) X is selected from:  a hydrogen,  an alkyl group, the number of carbons being from 1 to 20, in particular from 1 to 10,  a halogen chosen from Cl, Br, I, or an amphiphilic group chosen from an anionic group, such as the carboxylates -RC0 ₂ ^~ , the sulphates -RSO ₄ ^" , the sulphonates -RSO ₃ ^" , a cationic group, such as RNH ₃ ⁺ , in which R is an alkyl group the number of carbons being from 1 to 20, in particular from 1 to 10, for its use as a medicine. The product for use according to claim 1, wherein the calixarene corresponds to the calixarene represented by the following formula II: Formula II

The product for use according to claim 1 or 2, wherein said given antibiotic is selected from the group consisting of β-lactams, aminoglycosides, fluoroquinolones, fosfomycin, colimycin, rifampicin, tigecycline, or fusidic acid. The product for use according to claim 3, wherein said given antibiotic is selected from imipenem, piperacillin-tazobactam, penicillin G, cefotaxime, ceftazidime, tobramycin, gentamicin, ciprofloxacin, rifampicin, fosfomycin, colimycin, streptomycin, ticarcillin-clavulanic acid, tigecycline or fusidic acid. 5. Product for use according to one of claims 1 to 4, as a medicament in the treatment of pathologies involving a bacterial strain having a resistance to at least one determined antibiotic. 6. Product for use according to claim 5, in the treatment of pathologies involving a resistant bacterial strain belonging to a species selected from Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. 7. Product for use according to claim 6, in the treatment of pathologies involving a resistant bacterial strain chosen from:  a strain of Staphylococcus aureus of wild phenotype,  a strain of Meticillin Resistant Staphylococcus aureus (MRSA) without associated resistance, a strain of MRSA exhibiting resistance to aminoglycosides and fluoroquinolones, a strain of MRSA with resistance to aminoglycosides, fluoroquinolones, macro-lincosamides-synergistins and ofloxacin,  a strain of Escherichia coli of wild phenotype,  a strain of Escherichia coli producing ESBL (Extended Spectrum Beta-Lactamase) presenting resistance associated with aminoglycosides, with rifampicin and with trimethoprim-sulfamethoxazole,  a strain of Escherichia coli producing penicillinase without associated resistance,  a hyperproducing cephalosporinase Escherichia coli strain with resistance associated with aminoglycosides, quinolones and the trimethoprim-sulfamethoxazole combination,  a strain of Pseudomonas aeruginosa of wild phenotype,  a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams, to trimethoprim-sulfamethoxazole and to fosfomycin,  a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin,  - a mucosal strain of Pseudomonas aeruginosa with resistance to rifampicin and trimethoprim-sulfamethoxazole. 8. Product for use according to one of claims 5 to 7, in the treatment of pathologies belonging to the group consisting of nosocomial and / or community infections, such as abdominal infections, digestive infections, urinary tract infections, respiratory infections, neuro-meningeal infections, infections of the oropharyngeal sphere, genital infections, endocarditis, skin and soft tissue infections, osteoarticular infections, eye infections, septicemia or bacteremia. 9. Pharmaceutical composition comprising as active substance at least one compound according to any one of claims 1 to 8 in association with a pharmaceutically acceptable vehicle. 10. Product containing a given antibiotic selected from the group consisting of β-lactams, aminoglycosides, fluoroquinolones, fosfomycin, colimycin, rifampicin, tigecycline, or fusidic acid, and  a calixarene represented by the following formula I: Formula I

in which :  (i) n = an integer of 4 to 16,  (ii) m = an integer of 1 to 10,  (iii) X is selected from:  a hydrogen,  an alkyl group, the number of carbons being from 1 to 20, in particular from 1 to 10,  a halogen chosen from Cl, Br, I, or an amphiphilic group chosen from an anionic group, such as the carboxylates -RC0 ₂ ^~ , the sulphates -RSO ₄ ^" , the sulphonates -RSO ₃ ^" , a cationic group, such as RNH ₃ ⁺ , in which R is an alkyl group the number of carbons being from 1 to 20, in particular from 1 to 10, as a combination product, for simultaneous, separate or spread over time in therapy of pathologies involving at least one bacterial strain exhibiting resistance to at least one specific antibiotic, such as abdominal infections, digestive infections, urinary tract infections, Respiratory infections, neuromeningeal infections, infections of the oro-pharyngeal sphere, genital infections, endocarditis, skin and soft tissue infections, osteoarticular infections, aocular infections, septicemia or bacteremia. The combination product for use according to claim 10, wherein the calixarene corresponds to the calixarene represented by the following formula II: Formula II

The combination product for use according to claim 10 or 11, wherein said given antibiotic is selected from imipenem, piperacillin-tazobactam, penicillin G, cefotaxime, ceftazidime, tobramycin, gentamicin, ciprofloxacin. , rifampicin, fosfomycin, colimycin, streptomycin, ticarcillin-clavulanic acid, tigecycline or fusidic acid. 13. Combination product for use according to any one of claims 10 to 12, simultaneous, separated or spread over time in therapy of pathologies involving at least one resistant bacterial strain belonging to a species selected from Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. 14. Combination product for use according to claim 13, simultaneous, separated or spread over time in therapy of pathologies involving at least one resistant bacterial strain chosen from:  a strain of Staphylococcus aureus of wild phenotype,  a strain of Meticillin Resistant Staphylococcus aureus (MRSA) without associated resistance,  a strain of MRSA exhibiting resistance to aminoglycosides and fluoroquinolones, - a strain of MRSA with resistance to aminoglycosides, fluoroquinolones, macro-lincosamide-synergistines and ofioxacin a strain of Escherichia coli of wild phenotype, a strain of Escherichia coli producing ESBL (Extended Spectrum Beta-Lactamase) presenting resistance associated with aminoglycosides, with rifampicin and with trimethoprim-sulfamethoxazole,  a strain of Escherichia coli producing penicillinase without associated resistance,  a hyperproducing cephalosporinase Escherichia coli strain with resistance associated with aminoglycosides, quinolones and the trimethoprim-sulfamethoxazole combination,  a strain of Pseudomonas aeruginosa of wild phenotype,  a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams, to trimethoprim-sulfamethoxazole and to fosfomycin,  a strain of Pseudomonas aeruginosa exhibiting resistance to β-lactams (including carbapenems), aminoglycosides, trimethoprim-sulfamethoxazole and ciprofloxacin,  - a mucosal strain of Pseudomonas aeruginosa with resistance to rifampicin and trimethoprim-sulfamethoxazole.